title: A class of sulfonamides with strong inhibitory action against the α-carbonic anhydrase from Trypanosoma cruzi.
abstract: Trypanosoma cruzi, the causative agent of Chagas disease, encodes for an α-carbonic anhydrase (CA, EC 4.2.1.1) possessing high catalytic activity (TcCA) which was recently characterized (Pan et al. J. Med. Chem. 2013, 56, 1761-1771). A new class of sulfonamides possessing low nanomolar/subnanomolar TcCA inhibitory activity is described here. Aromatic/heterocyclic sulfonamides incorporating halogeno/methoxyphenacetamido tails inhibited TcCA with KIs in the range of 0.5-12.5 nM, being less effective against the human off-target isoforms hCA I and II. A homology model of TcCA helped us to rationalize the excellent inhibition profile of these compounds against the protozoan enzyme, a putative new antitrypanosoma drug target. These compounds were ineffective antitrypanosomal agents in vivo due to penetrability problems of these highly polar molecules that possess sulfonamide moieties.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Istanbul University , 34116, Beyazit, Istanbul, Turkey.
authors.forename: Özlen
authors.initials: Ö
authors.lastname: Güzel-Akdemir
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.forename: Peiwen
authors.initials: P
authors.lastname: Pan
authors.forename: Alane B
authors.initials: AB
authors.lastname: Vermelho
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000981:Antiprotozoal Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides